In recent years, medical instruments to be placed in the body such as percutaneous catheters have been used for medical treatment. For example, a percutaneous catheter is inserted inside a living body from outside the living body, in order to perform medical practices such as peritoneal dialysis. However, when the medical instrument to be placed in the body such as the percutaneous catheter is implanted in the living body, the medical instrument placed in the body is recognized as a foreign body by biological tissues. Therefore, the biological tissues and the medical instrument do not adhere tightly with each other. As a result, in the case of the percutaneous catheter for example, an epidermis sinks inwards along the catheter, so referred as a down-growth (phenomenon of which an epithelial sinks inwards along the surface of the catheter). The deepening of the down-growth causes insufficient disinfection. The insufficient disinfection creates an infection pathway for bacteria, which becomes a cause for inflammation of skin and other problems. Consequently, this causes a condition that in the end the medical instrument placed in the body has to be taken out from the body. For medical instruments to be placed in the body other than the percutaneous catheter, there is a problem that the medical instrument is moved in the body. In order to solve these problems, various medical instruments to be placed in the body have been proposed. The proposed medical instruments to be placed in the body are disclosed to have tight adhesiveness with the living body.
For example, intraperitoneal catheters and central venous catheters have a cuff member (Dacron cuff) made of Dacron nonwoven fabric in order to prevent bacterial infection and to fix the catheter to the living body (for example, see Patent Document 5). By implanting the Dacron cuff part under the skin, hyperplasia of hypodermic connective tissues occurs. Consequently, the catheter is firmly fixed. Because the catheter is securely fixed, the possibility of accidental evulsions is reduced. However, even with this catheter, the Dacron cuff and the biological tissues are not adhered together. Therefore, the bacterial infection is not completely prevented.
As another medical instrument to be placed in the body, a percutaneous terminal made of a highly bio-affinitive hydroxyapatite ceramics is proposed (see Non-Patent Document 2). However, the following problems exist in the arrangement of the disclosed conventional technique. In the arrangement of Non-Patent Document 2, the percutaneous terminal is formed from only a hydroxyapatite ceramics. Hydroxyapatite is a constituent of teeth and shows excellent bio-affinity with soft tissues, however the hydroxyapatite ceramics is hard and fragile. Therefore, the percutaneous terminal becomes hard. Consequently, a space may generate between the hydroxyapatite ceramics and the biological tissues when implanted inside the living body. This causes the problem of poor adhesiveness with the living body. Furthermore, if the percutaneous terminal is produced only with the hydroxyapatite ceramics, the percutaneous terminal becomes a large size. As such, various problems exist with the percutaneous terminal disclosed in Non-Patent Document 2, such that the percutaneous terminal is easily breakable, and discomfort is felt by patients due to the hardness of the percutaneous terminal when implanted inside the living body.
As another example, a method is proposed which modifies a highly bio-affinitive calcium phosphate on a surface of a base material of a medical device or a base material of a medical material, in order to allow tight adhesiveness with the living body. More specifically, for example, Patent Document 6 discloses a method which modifies the calcium phosphate on a surface of a base material of a medical component, by using sputtering ion beams. The medical component here is made of a polymer or the like. Patent Document 7 discloses a method which modifies the calcium phosphate on a surface of a base material made of glass, a ceramic calcium phosphate or the like, by soaking. Patent Document 8 discloses a method which precipitates the calcium phosphate on a surface of an inorganic biomaterial. Patent document 9 discloses a method which mechanically abuts the calcium phosphate or the like on a surface of a medical material by blasting or other methods. Patent document 10 discloses a method which modifies the calcium phosphate on a surface of a base material of a medical material such as an organic polymer or the like, by utilizing alternative soaking.
However, the calcium phosphate to be modified on the surface of the base material in the methods disclosed in Patent Documents 6 through 10 are all amorphous, which readily melts inside the living body. Therefore, the bio-affinity of the medical devices produced by using the medical materials described in Patent Documents 6 through 10 do not last for a long term inside the living body. As a result, the medical instruments are suitably used when the purpose of using the calcium phosphate is to melt the calcium phosphate in the body (for example, as a material to replace bones), however are not suitably used when the purpose of using the calcium phosphate is to keep the calcium phosphate inside the body for a long term (for example, the percutaneous terminal) or the like. In addition, the modifying method disclosed in Patent Documents 6 through 10 adhere the calcium phosphate to the base material either physically or electrostatically. This has the problem that adhering strength of the calcium phosphate is weak.
In order to attain the purpose of keeping the calcium phosphate inside the body for a long term, methods to modify a surface of a polymer base material with the calcium phosphate has been yearned for, and various proposals have been made. For example, methods such as the ones disclosed in Patent Documents 11 through 13 have been proposed. Patent Document 11 describes a method where ceramic porous particles made of hydroxyapatite are fixed on a surface of a polymer base material of an intraperitoneal catheter by using an adhesive, or by fusing the polymer base material. Patent Document 12 discloses a medical material in which a calcium phosphate such as hydroxyapatite is chemically bonded to a surface of a polymer base material. Patent Document 13 discloses a technique which coats an organic fiber aggregate or an inorganic fiber aggregate with a calcium phosphate compound, which is then jointed to an artificial trachea or the like.
However, if the porous particles made of highly bio-affinitive hydroxyapatite are adhered or fused on the surface of the catheter as described in Patent Document 11, the hydroxyapatite is applied directly to the catheter. This causes the problem that a part of the catheter where the hydroxyapatite is applied would differ in physical properties to the other parts of the catheter. In particular, if the porous particles made of hydroxyapatite are introduced to the catheter by fusing, the catheter would lose its physical properties and possibly break. If the hydroxyapatite is adhered directly to the catheter with an adhesive, problems arise such as the area of which the hydroxyapatite is exposed may decrease due to the soaking-in of the adhesive into the hydroxyapatite, or the hydroxyapatite may peel off from the catheter in case of insufficient adhering. If the fiber aggregate is coated with the calcium phosphate compound as described in Patent Document 13, the fiber which has not been coated with the calcium phosphate compound could possibly be exposed. In addition, this method requires to produce the fiber aggregate which is coated with the calcium phosphate and to join this coated fiber aggregate to a plastic body in advance. Thus, it is difficult to apply this method for a medical instrument and the like in complex shapes. Furthermore, Patent Document 13 forms the calcium phosphate by a liquid-phase precipitation method. The calcium phosphate formed by the liquid-phase precipitation method is amorphous. Therefore, the calcium phosphate readily melts inside the body. In addition, as described in paragraph [0012] of Patent Document 13, it is difficult to coat the calcium phosphate in a thickness of 1 μm or less. This is because it is industrially difficult to evenly coat the calcium phosphate in a thickness of 1 μm or less in a conventional liquid-phase precipitation method or other conventional methods. Furthermore, such thickness causes the calcium phosphate to readily melt inside the body.
In response to this, the inventors of the present invention independently developed a hydroxyapatite composite particle (see Patent Document 14). The hydroxyapatite composite particle is produced by chemically bonding a silk fibroin and the hydroxyapatite, and has high bio-affinity. Additionally, the inventors produced a percutaneous terminal which can adhere tightly to the living body, by adhering the hydroxyapatite composite particle to a surface of a substrate (see Non-Patent Document 3). The percutaneous terminal and a catheter provided with the percutaneous terminal can adhere to the living body far tighter compared to conventional percutaneous terminals.
A conventional and publicly known flocking method is referred as an electrostatic flocking or electrodeposition flocking. The flocking method is a processing method where short fibers (referred as ‘pile flock’ or ‘pile’) are orthogonally planted on a base material. An adhesive is applied to the base material in advance, and short fibers are planted by utilizing electrostatic attraction in a high voltage electrostatic field. The flocking method is not limited to simply planting short fibers, and various effects are attainable by selecting specific adhesives, short fibers, base materials and the like. Therefore, the method is utilized in a broad range of fields (see Non-Patent Document 1). For example, the flocking method is used in processing clothing and textile goods (for example, see Patent Documents 1 through 3). The flocking method is also used in processing makeup and cosmetic products (for example, see Patent Document 4) as well as processing elastic material such as rubber gloves (for example, see Patent Document 15). However, there have been no examples of which the flocking method is used for processing medical material. The technical idea itself of such process did not exist, to process flocking with short fibers on a surface of a medical instrument to be placed in the body such as a percutaneous catheter.
Non-Patent Document 1
“Shin Kobunshi Bunko 17 Furokku Kakou no Jissai (New Polymer Publishing 17 Facts of Flocking)”, N. Iinuma, Polymer Publishing Inc., p. 1, published Aug. 1, 1979,
Non-Patent Document 2
H. AOKI, in “Medical Applications of Hydroxyapatite” (Ishiyaku EuroAmerica, Inc., 1994) p. 133-155
Non-Patent Document 3
Tsutomu Fruzono, PhD, Shoji Yasuda, M S, Tsuyoshi Kimura, PhD, Singo Kyotani, M D, Junzo Tanaka, PhD, Akio Kishida, PhD, “Nano-scaled hydroxyapatite/polymer composite IV. Fabrication and cell adhesion properties of a three-dimensional scaffold made of composite material with a silk fibroin substrate to develop a percutaneous device”. J Artif Organs (2004) 7:137-144Patent Document 1Japanese Unexamined Patent Publication, Tokukaihei, No. 7-116557 (published May 9, 1995)Patent Document 2Japanese Unexamined Patent Publication, Tokuhyo, No. 2000-505845 (published May 16, 2000)Patent Document 3Japanese Unexamined Patent Publication, Tokukaihei, No. 6-141926 (published May 24, 1994)Patent Document 4Japanese Unexamined Patent Publication, Tokukai, No. 2003-38596 (published Feb. 12, 2003)Patent Document 5Japanese Unexamined Patent Publication, Tokukaihei, No. 8-206193 (published Aug. 13, 1996)Patent Document 6Japanese Unexamined Patent Publication, Tokukaihei, No. 8-56963 (published Mar. 5, 1996)Patent Document 7Japanese Unexamined Patent Publication, Tokukaihei, No. 7-306201 (published Nov. 21, 1995)Patent Document 8Japanese Unexamined Patent Publication, Tokukaisho, No. 63-270061 (published Nov. 8, 1988)Patent Document 9Japanese Unexamined Patent Publication, Tokukaihei, No. 7-303691 (published Nov. 21, 1995)Patent Document 10Japanese Unexamined Patent Publication, Tokukai, No. 2000-342676 (published Dec. 12, 2000)Patent Document 11Japanese Unexamined Patent Publication, Tokukaihei, No. 10-15061 (published Jan. 20, 1998)Patent Document 12Japanese Unexamined Patent Publication, Tokukai, No. 2001-172511 (published Jun. 26, 2001)Patent Document 13Japanese Unexamined Patent Publication, Tokukaihei, No. 06-327757 (published Nov. 29, 1994)Patent Document 14Japanese Unexamined Patent Publication, Tokukai, No. 2004-51952 (published Feb. 19, 2004)Patent Document 15U.S. Patent Application Publication No. 2004/0033334 (published Feb. 19, 2004)